The Iris + study: advanced MRI of the brain in changes of behavior

The second most common type of presenile dementia after Alzheimer*s disease is
frontotemporal dementia (FTD). Its prevalence is estimated to be 2.7/100,000
inhabitants in the Netherlands (Rosso et al., 2003). The most common
presentation of FTD is the syndrome characterized by progressive deterioration
in social and personal conduct (Neary et al., 1998), also referred to as
behavioral-variant FTD (bvFTD). Current diagnostic criteria are based on
clinical features such as behavioral disinhibition, apathy or inertia, loss of
sympathy or empathy and behavior that is perseverative, stereotyped or
compulsive. Hyperorality and dietary changes may also occur. The
neuropsychological profile is often characterized by executive dysfunction with
relative intact memory and visuospatial function (Rascovsky et al., 2007).
Striking is the patient*s lack of insight into or the concern for his or her
actions (McKhann et al., 2001) The underlying neuropathological changes found
post mortem all concern atrophy of the bilateral frontotemporal lobes (Piguet,
Hornberger, Mioshi, & Hodges, 2010). Surprisingly, in a subset of patients with
a clinical diagnosis of bvFTD, this focal atrophy is not found using structural
magnetic resonance imaging (MRI) (Kipps et al., 2007). For that reason, MRI
findings have until now only remained supportive in the eventual diagnosis of
FTD (McKhann et al., 2001; Neary et al., 1998). However, interest in this group
of patients with normal MRI despite a clinical bvFTD diagnosis has recently
increased as the absence of MRI abnormalities has been associated with a more
benign disease course than in patients with MRI abnormalities: whereas the
majority of patients with frontotemporal atrophy were dead or institutionalized
within 3 years, patients with no or borderline atrophy survived more than 9
years to institutionalization or death (Davies et al., 2006). This observation
has given rise to the debate whether these patients, despite fulfilling the
bvFTD diagnostic criteria, actually suffer from an underlying neurodegenerative
condition (Kipps, Hodges, & Hornberger, 2010). Such patients are therefore
considered to have the bvFTD *phenocopy* syndrome, i.e. presenting with the
characteristic behavioral features of bvFTD without progressing to actual
dementia.
Until now it remains unclear whether the etiology of the phenocopy bvFTD is
neurodegenerative or neuropsychiatric. One can assume however, given the
typical changes in these patients on a behavioral level, that changes are also
taking place on a neurophysiological level. Recent studies attempted to detect
these changes by in vivo imaging methods as structural MRI and positron
emission tomography (PET). As mentioned before, MRI scans of these patients do
not reveal any atrophy on MRI (Davies et al., 2006; Kipps et al., 2007) or
abnormal metabolism on PET scans (Kipps et al., 2009). For that reason, more
advanced neuroimaging techniques such as functional MRI (fMRI), resting state
fMRI, diffusion tensor imaging (DTI) and arterial spin labeling (ASL) may be
necessary to detect more subtle neurophysiological processes than changes in
volume and metabolism as found by MRI and PET, that can provide insight as to
why these patients are so severely impaired in social and interpersonal conduct.
With functional MR imaging (fMRI), activity of the brain can be measured
noninvasively. Brain activation during performance of cognitive tasks that are
associated with clinically affected domains may reveal differences in bvFTD
phenocopy patients and controls. Functional MRI can also be acquired when the
subject is not performing a task, i.e. at rest, to visualize brain activity in
the resting state (resting state fMRI). Spontaneous or baseline brain activity
measured by this type of imaging may differ between patients and controls.
With diffusion tensor imaging (DTI) the microstructure of the grey and white
matter can be assessed noninvasively. An increase of mean diffusivity (MD) and
reduction of fractional anisotropy (FA) may indicate loss of parenchymal
integrity, occurring prior to actual brain volume loss.
Arterial spin labelling (ASL) is a non-invasive MR imaging technique with which
brain perfusion can be measured quantitatively. ASL has several advantages over
PET and SPECT imaging, in terms of its non-invasiveness, higher spatial and
temporal resolution and quantitative properties. Its enhanced sensitivity may
pick up on changes in perfusion not found by PET.

The purpose of this study is to assess whether measures acquired with advanced
MRI neuroimaging can be used to differentiate between bvFTD phenocopy patients
and healthy controls. For each technique the research question is listed below:
1 - diffusion tensor imaging (DTI):
Do bvFTD phenocopy patients have different mean diffusivity (MD; increase) and
fractional anisotropy (FA; decrease) of (normal appearing) white matter
compared to healthy controls?
2 - functional MR imaging (fMRI):
Do bvFTD phenocopy patients have different patterns of brain activation during
the performance of cognitive tasks that are associated with clinically affected
domains compared to controls?
3 - resting state fMRI
Do bvFTD phenocopy patients have different patterns of brain activation during
rest compared to controls?
4 - arterial spin labeling (ASL):
Do bvFTD phenocopy patients have different brain perfusion compared to healthy
controls?

Case-control study

No permanent hazardous effects of exposure to a static magnetic field as used
in MR imaging have yet been demonstrated. Participants will be extensively
screened for contraindications by an experienced researcher upon inclusion in
the study.